bims-medebr 2025-12-28 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–12–28
sixteen papers selected by
Regina F. Fernández, Johns Hopkins University

Metabolic Astrocytic Support with Decanoic Acid Enhances Energy Metabolism in Alzheimer's Disease Models.
Where Is the Oxygen? The Mirage of Non-Oxidative Glucose Consumption During Brain Activity.
From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency Related to PDHA1 Variants.
The Crosstalk Between Brain Energy Metabolism and Neuropathic Pain: Mechanisms and Therapeutic Implications.
New Multiplex LC-MS/MS Method for lipid biomarker Analysis of Inherited Neurodegenerative Metabolic Diseases.
Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice.
Metabolism of glioblastoma: a review of metabolic adaptations and metabolic therapeutic interventions.
Aging Effects on Metabolic Sensor and Glycogen Metabolism in Old Male versus Female Rat Primary Hypothalamic Astrocyte Cultures.
SLC38A3 deficiency reveals a critical role of blood-derived glutamine in brain development.
Uncovering the Complexity of Synucleinopathies: An Ongoing Tale Between Proteins and Lipids.
Disruption of cerebral cholesterol homeostasis by PS-NPs: astrocytic endoplasmic reticulum stress.
The Lipidome of the Lateral Ventricle Choroid Plexus Exhibits Sex-Specific Changes Across Aging.
Mitochondrial Dysfunction in Alzheimer's disease: Focus on Dynamics and Electron Transport Chain.
The biochemical dynamics of the glycogen phosphatase laforin directly impact brain metabolism.
Mitochondrial dysfunction mediates the association between mercury exposure and lipid metabolism in children and adolescents.
Succinate Confers Stronger Cytoprotection in Kidney Cells than in Astrocytes Due to Its More Efficient Involvement in Energy Metabolism.

Cells. 2025 Dec 16. pii: 2007. [Epub ahead of print]14(24):

Metabolic Astrocytic Support with Decanoic Acid Enhances Energy Metabolism in Alzheimer's Disease Models.

Aishat O Ameen, Maja B Rindshøj, Katarina Stoklund Dittlau, Karin Borges, Kristine K Freude, Blanca I Aldana.

  Alzheimer's disease (AD) is increasingly recognized as a disorder of cerebral energy metabolism, where impaired glucose utilization contributes to disease pathology. Medium-chain fatty acids (MCFAs), such as decanoic acid (C10), have emerged as promising metabolic substrates due to their ability to bypass glycolytic deficits and support mitochondrial function. In this study, we investigated the metabolic impact of C10 in the 5xFAD mouse model of AD and in human induced pluripotent stem cell (hiPSC)-derived astrocytes carrying familial AD mutations. Utilizing stable 13C-labeled metabolic tracers, we demonstrated that while [U-13C]glucose metabolism was largely preserved in cortical slices of 6-month-old 5xFAD female mice, [1,2-13C]acetate uptake was significantly reduced, suggesting impaired astrocytic metabolism. [U-13C]C10 was efficiently metabolized in both WT and 5xFAD brain slices, particularly in astrocytes, as indicated by high labeling of glutamine and citrate. Furthermore, C10 competitively inhibited glucose and acetate metabolism, suggesting its potential as an auxiliary energy substrate. In hiPSC-derived astrocytes, AD-specific metabolic responses to C10 varied by mutation, with only partial alterations in oxidative glucose metabolism observed in APP and PSEN1 variants, highlighting genotype-dependent metabolic alterations. While AD-related mutations in the hiPSC models did not lead to robust deficits, the in vivo environment in the 5xFAD model is associated with measurable metabolic changes in astrocytes. These findings underscore astrocytic metabolic dysfunction in AD and suggest that C10 supplementation may restore brain energy by supporting astrocytic oxidative metabolism.

Keywords:  5xFAD mouse; Alzheimer’s disease; brain energy metabolism; decanoic acid; hiPSC-derived astrocytes; medium-chain fatty acids; mitochondria

DOI:  https://doi.org/10.3390/cells14242007
NeuroSci. 2025 Dec 09. pii: 126. [Epub ahead of print]6(4):

Where Is the Oxygen? The Mirage of Non-Oxidative Glucose Consumption During Brain Activity.

Avital Schurr.

  Ever since the discovery that neuronal tissue can utilize lactate as an aerobic substrate for mitochondrial adenosine triphosphate (ATP) production, a debate has ensued between those who have questioned the importance of lactate in brain energy metabolism and those who argue that lactate plays a central role in this process. The "neuron astrocyte lactate shuttle hypothesis" has sharpened this debate since it postulates lactate to be the oxidative energy substrate for activated neurons. Those who minimize lactate's role insist that a non-oxidative process they termed "aerobic glycolysis" supports brain activation, despite oxygen availability. To explain the paradox that the active brain would utilize the inefficient glycolysis over the much more efficient mitochondrial oxidative phosphorylation (OXPHOS) for ATP production, they suggested the "efficiency tradeoff hypothesis," where the inefficiency of the glycolytic pathway is traded for speed necessary for the information transfer of the active brain. In contrast, other studies reveal that oxidative energy metabolism is the process that supports brain activation, refuting both the "aerobic glycolysis" concept and the premise of the "efficiency tradeoff hypothesis". These studies also shed doubts on the usefulness of the blood oxygenation dependent functional magnetic resonance imaging (BOLD fMRI) method and its signal as an appropriate tool for the estimation of brain oxygen consumption, as it is unable to detect any oxygen present in the extravascular brain tissue.

Keywords:  BOLD fMRI; astrocyte; energy metabolism; glucose; glycolysis; lactate; neuron; oxidative phosphorylation; oxygen

DOI:  https://doi.org/10.3390/neurosci6040126
J Child Neurol. 2025 Dec 23. 8830738251404115

From Severe Neonatal Encephalopathy to Slowly Neurologic Progressive Disease: Pyruvate Dehydrogenase Deficiency Related to PDHA1 Variants.

Sofia Corbaz, Daniela Alejandra Pibernus, Mariana Amina Loos, María Mercedes Pérez, María Celeste Buompadre, Francisco Martín García, María Paula Rodriguez, Carlos Rugilo, Marisa Armeno, Go Hun Seo, Rin Khang, Cristina Noemi Alonso, Hilda Verónica Aráoz.

  Pyruvate dehydrogenase complex (PDC) deficiency is a rare mitochondrial disorder characterized by impaired oxidative metabolism, predominantly due to pathogenic variants in the PDHA1 gene. We present the clinical, biochemical, radiologic, and molecular characterization of 4 Argentine pediatric patients with PDHA1-related PDC deficiency, including a novel missense variant, c.260T>C p.(Ile87Thr). Clinical presentations ranged from severe neonatal encephalopathy with central apneas to a more slowly progressive neurodegenerative course in childhood. All patients exhibited lactic acidosis and structural brain abnormalities, with 3 fulfilling criteria for Leigh syndrome. Molecular studies identified 4 missense variants located in conserved regions of the E1α subunit. In silico analysis of the novel p.(Ile87Thr) variant suggested impaired thiamine pyrophosphate binding. All patients received thiamine and a ketogenic diet, with favorable outcomes in seizure control, neurodevelopment, and metabolic stability. Our findings expand the clinical and molecular spectrum of PDHA1-related PDC deficiency and underscore the importance of early diagnosis and targeted metabolic therapy. Furthermore, we report a previously undescribed radiologic pattern in one patient and propose potential structural implications of the novel variant based on protein modeling.

Keywords:  Ketogenic diet; Leigh syndrome; PDHA1; mitochondrial disease; pyruvate dehydrogenase deficiency

DOI:  https://doi.org/10.1177/08830738251404115
Metabolites. 2025 Nov 21. pii: 755. [Epub ahead of print]15(12):

The Crosstalk Between Brain Energy Metabolism and Neuropathic Pain: Mechanisms and Therapeutic Implications.

Jiangtao Wang, Baitong Liu, Jinyan Liu, Zhuoxi Hou, Guangxin Xie, Xiaoyi Xiong, Shuguang Yu.

  Normal physiological brain activity relies on precise and orderly energy supply. The brain's complex energy metabolism (encompassing glucose, lipid, lactate, and amino acid metabolic pathways) underpins neuronal function. Neuropathic pain severely impacts patients' quality of life, and traditional therapies often prove ineffective. This condition is frequently accompanied by energy metabolism disorders in relevant brain regions. Dysregulation of metabolic pathways disrupts neuronal energy supply and signaling, impairs synaptic transmission, and triggers abnormal glial interactions and neuroinflammation, thereby driving the onset and chronic progression of neuropathic pain. This paper systematically elucidates the impact of metabolic pathway imbalances on neuropathic pain and explores potential therapeutic strategies targeting energy homeostasis. It aims to provide novel theoretical foundations and treatment approaches for the clinical management of neuropathic pain.

Keywords:  amino acid metabolism; glucose metabolism; lactate metabolism; lipid metabolism; neuropathic pain

DOI:  https://doi.org/10.3390/metabo15120755
J Lipid Res. 2025 Dec 20. pii: S0022-2275(25)00230-5. [Epub ahead of print] 100967

New Multiplex LC-MS/MS Method for lipid biomarker Analysis of Inherited Neurodegenerative Metabolic Diseases.

Anna Sidorina, Giulio Catesini, Federica Deodato, Sara Boenzi, Diego Martinelli, Cristiano Rizzo, Carlo Dionisi-Vici.

  A significant number of inherited neurodegenerative metabolic diseases (NMD) arise from altered lipid metabolism, including impaired degradation of sphingolipids and dysfunction in organelle-related machineries involved in lipid processing and trafficking. These lipid dysregulations profoundly impact cellular membranes, signaling pathways, and myelin integrity, contributing to the complex and multisystemic clinical phenotypes characteristic of NMD, which often complicate diagnosis and delay treatment initiation. Here, we present a high-throughput, multiplex liquid chromatography-mass spectrometry (LC-MS/MS) method for the analysis of an extended panel of NMD biomarkers in plasma and dried blood spots. One-step sample extraction and targeted LC-MS/MS acquisitions in positive and negative ionization allowed the simultaneous meausurement of 13 diagnostic biomarkers associated with GM1 and GM2 gangliosidosis, Fabry, Gaucher, and Krabbe diseases, acid sphingomyelinase deficiency (ASMD), Niemann-Pick disease type C (NPC), X-linked adrenoleukodystrophy (X-ALD), peroxisomal biogenesis disorders (PBD, Zellweger syndrome), metachromatic leukodystrophy (MLD), and MEDNIK/MEDNIK-like syndromes, a disorder of cellular trafficking. The method was analytically and clinically validated, confirming the diagnosis of all targeted NMDs in samples from 89 patients. Additionally, the method allowed the differentiation of X-ALD from PBD and revealed the elevation of C18- and C16-sulfatides in Krabbe-disease and MEDNIK-syndromes, respectively. This multiplex assay enhances diagnostic efficiency and expands the discovery of novel biomarkers, enabling the quantification of diagnostic markers for a wide range of NMDs. The method is suitable for diagnosis of NMD, as a first- or second-tier test in neonatal screening, as confirmatory testing of variant of unknown significance in genetic panels and for longitudinal monitoring in treatable diseases.

Keywords:  Biomarker analysis; Brain lipids; Ceramides; Cerebrosides; Glycolipids; Lysophospholipid; Neurodegenerative metabolic diseases; Newborn screening; Sphingolipids; Tandem mass spectrometry

DOI:  https://doi.org/10.1016/j.jlr.2025.100967
EMBO Mol Med. 2025 Dec 22.

Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice.

Sahitya Ranjan Biswas, Porter L Tomsick, Colin Kelly, Brooke A Lester, Julia P Milner, Sara N Henry, Yairis Soto, Samantha Brindley, Nicole DeFoor, Paul D Morton, Alicia M Pickrell.

  Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Loss of Complex I significantly impacted neural stem cell proliferation, neuronal and oligodendroglial progeny, lineage progression, and displayed overt differences in specific brain regions across postnatal development. Our findings show that these disruptions in all categories occur specifically within the subventricular zone and corpus callosum prior to the age when these mice experience neurodegeneration. Given that LS is considered a neurodegenerative disease, we propose that there are neurodevelopmental signatures predating classic diagnosis in LS.

Keywords:  Corpus Callosum; Leigh Syndrome; Neural Stem Cells; Postnatal Neurogenesis; Subventricular Zone

DOI:  https://doi.org/10.1038/s44321-025-00367-4
Front Oncol. 2025 ;15 1712576

Metabolism of glioblastoma: a review of metabolic adaptations and metabolic therapeutic interventions.

James Chung, Jawad Saad, Ahmad Kafri, Julien Rossignol, Maxwell Verbrugge, Jesse Bakke.

  Glioblastoma (GBM) is the most common and aggressive primary malignancy of the central nervous system, marked by profound metabolic reprogramming that promotes growth, invasion, and therapeutic resistance. This review examines metabolic adaptations that sustain GBM progression and summarizes current and emerging strategies that target these pathways. GBM cells display increased aerobic glycolysis, glutaminolysis, lipid and cholesterol synthesis, and mitochondrial remodeling. These processes are regulated by oncogenic alterations such as EGFR amplification, PTEN loss, and HIF-1α stabilization, which allow tumor cells to thrive in hypoxic and nutrient-poor environments. Accumulation of lactate further supports metabolic flexibility and promotes an immunosuppressive microenvironment. Recent studies have focused on exploiting these metabolic vulnerabilities through dietary, pharmacologic, and oxygen-modulating interventions. The ketogenic diet has been explored as an adjuvant therapy to reduce glucose availability and enhance treatment sensitivity. Pharmacologic approaches include inhibition of key metabolic enzymes such as hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase, and glutaminase. Additional strategies aim to disrupt mitochondrial function through VDAC1 blockade or to reduce tumor hypoxia using hypoxia-activated prodrugs, hyperbaric oxygen therapy, and oxygen-transporting agents. Preclinical findings suggest these approaches can suppress tumor proliferation and improve responsiveness to radiation and chemotherapy, although clinical evidence remains limited. Combining metabolic interventions with standard therapies may help overcome GBM's intrinsic resistance and metabolic plasticity. Overall, the review highlights metabolism as a key determinant of GBM pathophysiology and a promising target for therapeutic innovation, emphasizing the importance of continued translational research to identify and exploit context-specific metabolic vulnerabilities in this highly lethal disease.

Keywords:  brain cancer; cancer; cancer signaling; glioblastoma; metabolic therapeutics; metabolism

DOI:  https://doi.org/10.3389/fonc.2025.1712576
Neuroglia. 2025 Dec;6(4):

Aging Effects on Metabolic Sensor and Glycogen Metabolism in Old Male versus Female Rat Primary Hypothalamic Astrocyte Cultures.

Rami Shrestha, Madhu Babu Pasula, Karen P Briski.

   Background/Objectives: Compartmentalized glucose metabolism in the brain contributes to neuro-metabolic stability and shapes hypothalamic control of glucose homeostasis. Glucose transporter-2 (GLUT2) is a plasma membrane glucose sensor that exerts sex-specific control of hypothalamic astrocyte glucose and glycogen metabolism. Aging causes counterregulatory dysfunction.
Methods: Current research used Western blot and HPLC-electrospray ionization-mass spectrometry to investigate whether aging affects GLUT2-dependent hypothalamic astrocyte metabolic sensor and glycogen enzyme protein expression and glycogen mass according to sex.
Results: Data document GLUT2-dependent up-regulated glucokinase (GCK) protein in glucose-deprived old male and female astrocyte cultures, unlike GLUT2 inhibition of this protein in young astrocytes. Glucoprivation of old male and female astrocytes caused GLUT2-independent down-regulation of 5'-AMP-activated protein kinase (AMPK) protein, indicating loss of GLUT2 stimulation of this protein with age. This metabolic stress also caused GLUT2-dependent suppression of phospho-AMPK profiles in each sex, differing from GLUT2-mediated glucoprivic enhancement of activated AMPK in young male astrocytes and phospho-AMPK insensitivity to glucoprivation in young female cultures. GS and GP isoform proteins were refractory to glucoprivation of old male cultures, contrary to down-regulation of these proteins in young glucose-deprived male astrocytes. Aging elicited a shift from GLUT2 inhibition to stimulation of male astrocyte glycogen accumulation and caused gain of GLUT2 control of female astrocyte glycogen.
Conclusions: Outcomes document sex-specific, aging-related alterations in GLUT2 control of hypothalamic astrocyte glucose and ATP monitoring and glycogen mass and metabolism. Results warrant future initiatives to assess how these adjustments in hypothalamic astrocyte function may affect neural operations that are shaped by astrocyte-neuron metabolic partnership.

Keywords:  AMPK; GLUT2 siRNA; LC-MS; glycogen; glycogen phosphorylase

DOI:  https://doi.org/10.3390/neuroglia6040041
Brain. 2025 Dec 24. pii: awaf473. [Epub ahead of print]

SLC38A3 deficiency reveals a critical role of blood-derived glutamine in brain development.

Inna Radzishevsky, Lama Harb, Maali Odeh, Inon Maoz, Aseel Saeed, Ankita Lahkar, Bella Agranovich, Ifat Abramovich, Farrukh A Chaudhry, Avi Avital, Daniel J Liebl, Herman Wolosker.

  Biallelic mutations in SLC38A3 lead to postnatal progressive microcephaly, epilepsy, and intellectual disability. However, the underlying pathophysiology remains unknown. Here, we identified Slc38a3 expressed at the vascular endothelium as a critical glutamine transporter that mediates blood-to-brain influx of glutamine through the blood-brain barrier (BBB). Endothelial selective deletion of Slc38a3 (Slc38a3-cKO) lowered the influx of glutamine across the BBB and decreased brain glutamine levels in mouse pups. This was associated with lower transfer of glutamine carbons to glutamate and GABA, suggesting impairment of the glutamine-glutamate/GABA metabolic cycle. Like individuals with mutations in SLC38A3, Slc38a3-cKO pups developed postnatal progressive microcephaly as well as behavioural impairments and morphological alterations in synapses. Approximately 30% of Slc38a3-cKO pups fail to thrive, exhibiting motor dysfunction and preweaning lethality. Glutamine deficiency in the Slc38a3-cKO hippocampus was associated with a slower TCA cycle and a seemingly adaptive increase in glycolysis rate. Glutamine supplementation replenished brain glutamine, prevented microcephaly, and normalized motor behavior in Slc38a3-cKO pups, indicating that brain glutamine deficiency is the primary cause of the phenotype. In contrast to the dogma that all glutamine is produced locally in the brain, our data show that Slc38a3 provides blood-derived glutamine for neurotransmitter synthesis, energy metabolism, and synaptogenesis. Our findings suggest that SLC38A3 mutations cause a glutamine-related BBB aminoacidopathy and developmental disorder, which may be amenable to glutamine supplementation therapy.

Keywords:  SN1; SNAT3; amino acid transporters; glutamatergic transmission; glutamine-glutamate/GABA cycle; microcephaly

DOI:  https://doi.org/10.1093/brain/awaf473
Mov Disord. 2025 Dec 26.

Uncovering the Complexity of Synucleinopathies: An Ongoing Tale Between Proteins and Lipids.

Manuel Flores-León, Tiago F Outeiro.

  Neurodegenerative diseases are pathological states characterized by progressive alterations in brain homeostasis during aging. Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are defined neuropathologically by the accumulation of inclusions known as Lewy bodies and Lewy neurites. These structures have complex compositions that, in addition to α-synuclein (aSyn), encompass a lipid core and nucleic acids, suggesting that proteostasis imbalances alone may not fully explain the origin of the pathognomonic inclusions. Recent research is uncovering the role of lipids in early disease stages. Imbalances in lipidostasis may arise as a consequence of lifestyle behaviors, impaired function or expression of central metabolic enzymes, or most likely, from a combination of both. Multiple experimental approaches and models have been used to investigate the underlying mechanisms associated with changes in both lipid-related enzymes and lipid species profiles seen in patients with synucleinopathies. However, our understanding of such mechanisms is still incomplete, especially in the context of humans, where mechanistic studies are not possible. Therefore, in this review, we highlight the latest research on aSyn-lipid interaction across different experimental models and propose that early disruptions in neuronal lipid metabolism can lead to altered membrane composition, contributing to the aggregation and accumulation of aSyn. Ultimately, we posit that elucidating the role of lipids in synucleinopathies may enable not only further patient classification but also the development of personalized treatment approaches. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  Lipid–protein interactions; Parkinson's disease; synucleinopathy

DOI:  https://doi.org/10.1002/mds.70167
J Nanobiotechnology. 2025 Dec 24.

Disruption of cerebral cholesterol homeostasis by PS-NPs: astrocytic endoplasmic reticulum stress.

Lei Tian, Yizhe Wei, Jianping Ma, Yiming Zhao, Yanan Mi, Leili Zhang, Bingyan Wang, Jiang Chen, Kang Li, Yue Shi, Wenqing Lai, Huanliang Liu, Bencheng Lin.

  Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. However, limited research has been conducted on the effects of polystyrene nanoplastic (PS-NPs) on intracranial cholesterol metabolic pathways. In this study, we exposed whole-brain organoids (WBOs) to PS-NPs and identified significant changes in endoplasmic reticulum stress and cholesterol biosynthesis pathways through whole-transcriptome sequencing. To investigate potential mechanisms of altered cholesterol pathways, we constructed a Transwell neuronal-astrocyte co-culture model. Results demonstrated that PS-NPs induced significant endoplasmic reticulum stress in astrocytes, specifically manifested by elevated levels of ATF4 and CHOP, along with increased autophagy indicated by the elevated LC3-II/I ratio. PS-NPs significantly inhibited the AKT/ACLY pathway of cholesterol biosynthesis, leading to marked reductions in acetyl-CoA and cholesterol within astrocytes (P < 0.05). In addition, PS-NPs led to a significant reduction of apolipoprotein APOE, which hindered cholesterol transport and ultimately inhibited synaptin (SYN) formation. In summary, PS-NPs induce endoplasmic reticulum stress and autophagy in astrocytes, impair cholesterol de novo synthesis and apolipoprotein-mediated transport, ultimately inhibiting neuronal synaptogenesis. Furthermore, specific inhibition of ERs restored cholesterol synthesis in astrocytes and neuronal synapses. This study demonstrates that PS-NPs produce neurotoxic effects by affecting cholesterol homeostasis in the brain.

Keywords:  Astrocytes; Cholesterol; Endoplasmic reticulum stress; Nanoplastics

DOI:  https://doi.org/10.1186/s12951-025-03949-z
J Neurochem. 2025 Dec;169(12): e70329

The Lipidome of the Lateral Ventricle Choroid Plexus Exhibits Sex-Specific Changes Across Aging.

Gaby Loupiac, Bijou Andriambelo, Jessica Avila-Lopez, Annick Vachon, Mariano Avino, Javier Rocha Ahumada, Stéphanie Miard, Frédéric Picard, Yunping Qiu, Irwin J Kurland, Benoit Laurent, Mélanie Plourde.

  During aging, the brain's lipid composition and the cerebrospinal fluid (CSF) secreted by the choroid plexus (ChP) undergo significant modifications. The ChP, an epithelial tissue located in each brain ventricle, experiences a decline in key functions, including protein secretion and CSF production. A critical gap in our understanding of the ChP lies in its lipid composition and the potential impact of age-related changes on its physiology. This study hypothesized that the lipidome of the lateral ventricle choroid plexus (LVCP) is modulated during aging, potentially generating pro-inflammatory mediators. To address this, we performed quantitative lipidomics on LVCP from male and female mice across aging and investigated whether pro-inflammatory lipid mediators increase with age. LVCP and cortex tissues from C57BL/6 mice aged 6, 12, 18, and 24 months (n = 5/age/sex) were analyzed using liquid chromatography-tandem mass spectrometry, and data were processed using Lipidr and univariate statistical methods. Given the pronounced sex differences, analyses were stratified by sex. During aging, 9 lipids in males and 19 in females were significantly modulated. In males, most changes occurred at 24 months and involved higher levels of arachidonic acid (ARA) in alkyl ether and plasmalogen phosphatidylcholine species. In females, most changes occurred at 18 months and were characterized by lower levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), whereas at 24 months, females exhibited higher levels of EPA, DHA, and ARA in alkyl ether and plasmalogens compared to other ages. Additionally, younger females showed higher levels of oxygenated derivatives of linoleic acid compared to older females. These findings reveal dynamic, sex-specific remodeling of the LVCP lipidome during aging, suggesting that lipid homeostasis in this structure is tightly regulated and may influence inflammatory signaling and barrier function in an age-dependent manner.

Keywords:  aging; choroid plexus; cortex; lateral ventricle; lipid mediators; lipidomics; lipids; mice; transcriptomics

DOI:  https://doi.org/10.1111/jnc.70329
Aging Dis. 2025 Dec 21.

Mitochondrial Dysfunction in Alzheimer's disease: Focus on Dynamics and Electron Transport Chain.

Jiehui Li, Gajendra Kumar, Yuqing Yan, Mengmeng Wang, Ling Xu, Haige Wu, Ye Gao, Yi Wang, Yingyi Fan, Ying Bai.

Alzheimer's disease (AD) is a progressive neurological disease characterized by a decline in cognitive abilities and memory loss. Mitochondrial dysfunction is a major factor in early pathological changes; however, its precise pathogenic mechanisms are not yet fully understood. Mitochondria are essential for neuronal energy generation, calcium ion balance regulation, apoptosis control, and production of reactive oxygen species. Among the various mitochondrial changes, the imbalance between fission and fusion is closely linked to β-amyloid deposition and tau pathology, forming a vicious cycle. The electron transport chain (ETC) produces more than 90% of cellular ATP and is damaged in AD. However, most studies simply refer to "mitochondrial dysfunction" in general terms without detailing specific changes in ETC complexes and their subunits. This review aims to provide a detailed overview of the dynamics and ETC complex dysfunction observed in AD for therapeutic targets.

DOI: https://doi.org/10.14336/AD.2025.1046
J Biol Chem. 2025 Dec 22. pii: S0021-9258(25)02949-7. [Epub ahead of print] 111097

The biochemical dynamics of the glycogen phosphatase laforin directly impact brain metabolism.

M Kathryn Brewer, Katherine J Donohue, Pankaj K Singh, Madushi Raththagala, Zoe R Simmons, Jeremiah L Wayne, Sheng Li, Rosa Viana, Dyann M Segvich, Christopher J Contreras, Alex R Cantrell, Pascual Sanz, Ramon C Sun, Craig W Vander Kooi, Peter J Roach, Anna DePaoli-Roach, Matthew S Gentry.

  Laforin is the only known glycogen phosphatase. Mutations in the laforin gene lead to the fatal childhood dementia and progressive myoclonic epilepsy known as Lafora disease (LD). A hallmark of LD is aberrant, cytoplasmic, glycogen-like aggregates known as Lafora bodies (LBs). Surprisingly, recent reports indicate that overexpression of a phosphatase-deficient laforin mutant, with the catalytic cysteine mutated to serine (LCS) rescued the formation of LBs in a laforin knockout mouse model. This finding led to questions regarding the biological relevance of laforin phosphatase activity and its role in LD etiology. In this study, we defined the in vitro and in vivo effects of the LCS mutation. LCS protein lacks catalytic activity but exhibits significantly higher binding to phosphate and long glucan chains compared to wild-type (WT) laforin. Additionally, LCS exhibits altered dynamics via hydrogen-deuterium exchange mass spectrometry and interacts more robustly with its binding partners malin and Protein Targeting to Glycogen (PTG). We demonstrate that these altered dynamics result in aberrant retention of the LCS protein in the brain of LCS knock-in mouse model, compared to laforin levels in wild-type (WT) mice. To examine the metabolic consequences of these biophysical changes, we compared the brain metabolomic phenotypes of LCS mice to WT and laforin knockout (LKO) mice. Furthermore, LCS mice display a distinct and significant global perturbation in metabolism. These results indicate a key signaling role for glycogen phosphorylation in glycogen metabolism, revealing an important biological role for laforin catalytic phosphatase activity.

Keywords:  Glycogen; Glycogen Storage Disease; Lafora disease (LD); Metabolomics; Phosphatase

DOI:  https://doi.org/10.1016/j.jbc.2025.111097
Lipids Health Dis. 2025 Dec 23. 24(1): 388

Mitochondrial dysfunction mediates the association between mercury exposure and lipid metabolism in children and adolescents.

Ping Cheng, Chen Liu, Jie Xiang, Peiwei Xu, Min Nian.



Keywords:  Adolescent; Lipids; Mercury; Mitochondria

DOI:  https://doi.org/10.1186/s12944-025-02843-9
Biochemistry (Mosc). 2025 Dec;90(12): 1985-1998

Succinate Confers Stronger Cytoprotection in Kidney Cells than in Astrocytes Due to Its More Efficient Involvement in Energy Metabolism.

Marina I Buyan, Kseniia S Cherkesova, Anna A Brezgunova, Irina B Pevzner, Nadezda V Andrianova, Egor Y Plotnikov.

  Being among the most metabolically active organs, brain and kidneys critically depend on efficient energy metabolism, which primarily relies on oxidative phosphorylation. Acute pathological conditions associated with a lack of metabolic substrates or their impaired utilization trigger signaling cascades that initiate cell death and lead to poorly reversible organ dysfunction. One of the therapeutic approaches to correct the energy deficit is administration of exogenous metabolites of the tricarboxylic acid cycle, such as succinate. In this study, we investigated the effects of exogenous succinate on astrocytes and renal epithelial cells under normal conditions and in serum deprivation-induced injury. Incubation with succinate increased the viability of both cell types under normal and pathological conditions, but a more pronounced cytoprotective effect was observed in renal cells. In injured renal epithelial cells, succinate increased mitochondrial membrane potential, a critical parameter for the maintenance of mitochondrial function and ATP generation. Comparison of respiration and oxidative phosphorylation parameters in astrocytes and renal epithelial cells in the presence of exogenous succinate revealed that epithelial cells exhibited a significantly higher respiratory control and lower proton leak compared to astrocytes, which correlated with the higher cytoprotective activity of succinate for kidney cells. Therefore, succinate showed a noticeable positive effect in the renal epithelium both under normal conditions and after serum deprivation; however, in astrocytes, its effect was less pronounced. This discrepancy might be related to a more efficient succinate utilization by the mitochondria in renal cells and intrinsic bioenergetic differences between astrocytes and epithelial cells. Despite the clinical use of succinate-containing drugs, the determination of optimal dosages and development of effective therapeutic regimens require further investigation. Our results demonstrate cell type-dependent differences in the efficacy of succinate, suggesting that its therapeutic potential may differ significantly depending on the organ-specific bioenergetic and metabolic properties.

Keywords:  apoptosis; astrocytes; brain; energy substrates; kidneys; mitochondria; oxidative phosphorylation; succinate

DOI:  https://doi.org/10.1134/S0006297925602539